Insulin-like growth factor 1 (IGF-1, somatomedin) is a small single-chain protein that induces muscle hypertrophy and blocks skeletal muscle atrophy. IGF-1 is initially synthesized in the human body as an IGF-1/E precursor, where E is an extension peptide at the C-terminus of the mature IGF-1 protein. The mature IGF-1 is initially encoded by one of three known splice variant mRNAs. The open reading frame of each mRNA encodes a precursor protein containing the 70 amino acid IGF-1 moiety and a particular extension (E) peptide at the C-terminus, which can be Ea, Eb or Ec, depending on the particular IGF-1 mRNA. The C-terminus E peptide is later cleaved as IGF-1 matures.
Modified recombinant human IGF-1/E proteins have been constructed and described in published PCT patent application WO2007/146689. These modified IGF-1/E peptides have longer half-life, increased stability, reduced affinity to inhibitory insulin-like growth factor binding proteins (IGFBPs), and increased efficacy compared to wild type IGF-1. An exemplary modified human IGF-1/E protein is hIGF-1/Ea 3mut (see FIG. 1). The “3mut” designation refers to a hIGF-1-E-peptide precursor having the following three sots of modifications: (1) deletion of G1, P2, and E3; (2) mutation of Arg 37 to Ala (R37A); and (3) deletion of R71 and S72. These hIGF-1/E 3mut peptides are proposed as being potential new drug for the treatment of skeletal muscle atrophy.
However, assessing the pharmacokinetics (PK) and pharacodynamics (PD) for this drug candidate is difficult, because the wild type and modified hIGF-1/E peptides differ with each other in only one or two amino acids at three separate positions over the length of the entire peptide chains (FIG. 1). No commercially available antibody recognizes the hIGF-1/Ea 3mut peptides without also detecting the endogenous hIGF-1.